A 7-week-old boy who was born at 31 weeks of gestation in a twin pregnancy developed respiratory distress and received positive pressure mechanical ventilation (PEEP: 4 cm of H2O). Initial findings on chest radiography revealed a large cystic abnormality within the right hemithorax, and diffuse infiltrates within the right upper lobe and throughout the left lung. He was also reported to have bilateral pneumothoraces. A right upper lobe resection was performed to investigate the nature of the cyst. Hematoxylin and eosin-stained sections of the lung parenchyma are shown in Figures 1-7.
The correct answer is ...
Pulmonary interstitial emphysema.
Pulmonary interstitial emphysema is an acquired condition that is caused by dissection of air out of alveolar spaces and into the loose connective tissue of the interlobular septa, the bronchovascular bundles, and the pleura, that in most cases occurs in mechanically ventilated in infants who require respiratory support, but can also be seen in adults.1 The pathogenesis of this condition was first proposed by Dr. Charles Macklin in 1939, who performed experiments in intubated cats, and observed dissection of air throughout the branches of hilar vessels after the instillation of high-pressurized air into the animals’ trachea.2
In a study performed in 205 infants weighting less than 1,500 g at birth, who had been admitted to the neonatal intensive care unit of the King's College Hospital in London,3 pulmonary interstitial emphysema affected 32% of premature infants weighing <1,500 g and occurred at a higher frequency (42%; p<0.02) in infants who weighted <1,000 g at birth. In addition, the same study found that this condition was significantly associated with hyaline membrane disease with and without ventilation (p<0.0005, p<0.025, respectively), with mechanical ventilation in cases that did not present with hyaline membrane disease (p<0.05), and in infants who develop a pneumothorax (p<0.001).3 When severe, the condition may also lead to the development of pneumomediastinum and pneumopericardium.1
Grossly, cyst-like spaces may be noted on the pleural surface, around large bronchovascular bundles, and particularly where interlobular septa intersect the pleura.4 In histological sections, multiple cystic spaces of different dimensions are identified throughout the parenchyma. The cystic spaces diffusely dissect into the loose connective tissue of the subpleural spaces (figure 1), the bronchovascular bundles (figures 2-3), and the interlobular septa (figure 4). A dominant cyst, or larger cysts may also be present (figure 5). Focally, the cysts may form interconnected channels which surround the bronchovascular bundles (figure 6). This condition can be either localized or diffuse, and acute or chronic.5
The histological findings in pulmonary interstitial emphysema vary with the age of the lesion. In acute cases, there are rents in the interstitium in the septa, subpleural space and bronchovascular bundles, that at first glance resemble tissue tears and artifacts.5 When the condition persists for longer time,5,6,7 the cysts develop a poorly formed capsule composed of loose collagen, granulation tissue, and a prominent foreign-body cell reaction composed of histiocytes and multinucleated giant cells protruding into the cystic space (figures 3, 4, and 7).8 No epithelial lining is identified within the cyst's lumina. Prominent fresh hemorrhage may also be seen dissecting throughout the cyst’s walls, the interlobular septa, the subpleural spaces, and the bronchovascular bundles (figures 2, 3, and 7).
The differential diagnosis includes other conditions that cause cystic lung disease in infants, including congenital pulmonary airway malformation (CPAM) also known as congenital cystic adenomatoid malformation (CCAM), infantile lobar emphysema, diffuse pulmonary lymphangiectasia, and diffuse pulmonary lymphangiomatosis. The distinction between pulmonary interstitial emphysema and these four entities is histologic.
In CPAM the cystic spaces are lined by an epithelial layer that can be pseudostratified, columnar to cuboidal (CPAM 0-III), or flat (CPAM IV). In addition, cartilage may be present adjacently to the cysts in some types of CPAM (CPAM 0 and I). The granulomatous reaction seen in pulmonary interstitial emphysema is not present in CPAM.5
Infantile lobar emphysema can get confused on imaging and grossly with pulmonary interstitial emphysema. However, both conditions are easily distinguished between each other on histological grounds. In infantile lobar emphysema, no real “cysts” are seen on tissue sections. Instead, there is marked dilatation of alveoli and terminal bronchioles resembling adult lung parenchyma. The airspace dilatation is the result of marked inflation differences that occur between adjacent lung lobes.5
In diffuse pulmonary lymphangiectasia and diffuse pulmonary lymphangiomatosis, the cyst-like spaces correspond to lymphatic channels lined by lymphatic endothelial cells that may be diffusely dilated in pulmonary lymphangiectasia or may form anastomosing variably sized spaces pulmonary lymphangiomatosis. As in CPAM, a granulomatous reaction in the spaces would be absent. The presence of the endothelial lining can be seen on H&E-stained tissue sections or can be highlighted by immunohistochemistry directed to endothelial markers (e.g., D2-40, CD31).5,9
1. Jalota Sahota R, Anjum F. Pulmonary interstitial emphysema. 2022. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560484/
2. Macklin CC. Transport of air along sheaths of pulmonic blood vessels from alveoli to mediastinum: Clinical implications. Arch Intern Med. 1939;64:913–26.
3. Hart SM, McNair M, Gamsu HR, Price JF. Pulmonary interstitial emphysema in very low birthweight infants. Arch Dis Child. 1983;58:612-5.
4. Stocker JT, Madewell JE. Persistent interstitial pulmonary emphysema: another complication of the respiratory distress syndrome. Pediatrics. 1977;59:847-57.
5. Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. (2002) Non-neoplastic disorders of the lower respiratory tract, AFIP Atlas of Nontumor Pathology, First Series, Fascicle 2. Washington, DC: American Registry of Pathology and the Armed Forces Institute of Pathology.
6. Stocker JT, Madewell JE. Persistent interstitial pulmonary emphysema: another complication of the respiratory distress syndrome. Pediatrics. 1977;59:847-57.
7. Stocker JT, Drake RM, Madewell JE. Cystic and congenital lung disease in the newborn. Perspect Pediatr Pathol. 1978;4:93-154.
8. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 30-1997. A preterm newborn female triplet with diffuse cystic changes in the left lung. N Engl J Med. 1997;337:916-24. 9. Boland JM, Tazelaar HD, Colby TV, Leslie KO, Hartman TE, Yi ES. Diffuse pulmonary lymphatic disease presenting as interstitial lung disease in adulthood: report of 3 cases. Am J Surg Pathol. 2012;36:1548-54.
Julian Villalba Nunez, M.D.
Fellow, Pulmonary Pathology
Ying-Chun Lo, M.D., Ph.D.
Senior Associate Consultant, Anatomic Pathology
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science